Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 DOI 10.1186/s12970-017-0173-z

REVIEW Open Access International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine Richard B. Kreider1*, Douglas S. Kalman2, Jose Antonio3, Tim N. Ziegenfuss4, Robert Wildman5, Rick Collins6, Darren G. Candow7, Susan M. Kleiner8, Anthony L. Almada9 and Hector L. Lopez4,10

Abstract Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson’s, Huntington’s disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads. Additionally, researchers have identified a number of potentially beneficial clinical uses of creatine supplementation. These studies show that short and long-term supplementation (up to 30 g/day for 5 years) is safe and well-tolerated in healthy individuals and in a number of patient populations ranging from infants to the elderly. Moreover, significant health benefits may be provided by ensuring habitual low dietary creatine ingestion (e.g., 3 g/day) throughout the lifespan. The purpose of this review is to provide an update to the current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to update the position stand of International Society of Sports Nutrition (ISSN). Keywords: Ergogenic aids, Performance enhancement, Sport nutrition, Athletes, Muscular strength, Muscle power, Clinical applications, Safety, Children, Adolescents

Background concussion and/or spinal cord neuroprotection. A number Creatine is one of the most popular nutritional ergogenic of clinical applications of creatine supplementation have aids for athletes. Studies have consistently shown that also been studied involving neurodegenerative diseases creatine supplementation increases intramuscular creatine (e.g., muscular dystrophy, Parkinson’s, Huntington’s concentrations, can improve exercise performance, and/or disease), diabetes, osteoarthritis, fibromyalgia, aging, brain improve training adaptations. Research has indicated that and heart ischemia, adolescent depression, and pregnancy. creatine supplementation may enhance post-exercise recov- The purpose of this review is to provide an update to the ery, injury prevention, thermoregulation, rehabilitation, and current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to * Correspondence: [email protected] update the position stand of International Society of Sports 1Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department Nutrition (ISSN) related to creatine supplementation. of Health & Kinesiology, Texas A&M University, College Station, TX 77843-4243, USA Full list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 2 of 18

Metabolic role reported to have lower intramuscular creatine stores (90– Creatine, a member of the guanidine phosphagen family, is 110 mmol/kg of dry muscle) and therefore may observe a naturally occurring non-protein amino acid compound greater gains in muscle creatine content from creatine found primarily in red meat and seafood [1–4]. The major- supplementation [11, 13, 20, 21]. Conversely, larger ath- ity of creatine is found in skeletal muscle (~95%) with small letes engaged in intense training may need to consume 5– amounts also found in the brain and testes (~5%) [5, 6]. 10 g/day of creatine to maintain optimal or capacity whole About two thirds of intramuscular creatine is phosphocrea- body creatine stores [22] and clinical populations may tine (PCr) with the remaining being free creatine. The total need to consume 10–30 g/day throughout their lifespan creatine pool (PCr + Cr) in the muscle averages about to offset creatine synthesis deficiencies and/or provide 120 mmol/kg of dry muscle mass for a 70 kg individual [7]. therapeutic benefit in various disease states [13, 19, 23]. However, the upper limit of creatine storage appears to be Phosphagens are prevalent in all species and play an im- about 160 mmol/kg of dry muscle mass in most individuals portant role in maintaining energy availability [1, 2, 24, 25]. [7, 8]. About 1–2% of intramuscular creatine is degraded Theprimarymetabolicroleofcreatineistocombinewith into creatinine (metabolic byproduct) and excreted in the a phosphoryl group (Pi) to form PCr through the enzym- urine [7, 9, 10]. Therefore, the body needs to replenish atic reaction of creatine kinase (CK). Wallimann and col- about 1–3 g of creatine per day to maintain normal leagues [26–28] suggested that the pleiotropic effects of Cr (unsupplemented) creatine stores depending on muscle are mostly related to the functions of CK and PCr (i.e., mass. About half of the daily need for creatine is obtained CK/PCr system). As adenosine triphosphate (ATP) is de- from the diet [11]. For example, a pound of uncooked beef graded into adenosine diphosphate (ADP) and Pi to pro- and salmon provides about 1–2 g of creatine [9]. The vide free energy for metabolic activity, the free energy remaining amount of creatine is synthesized primarily in released from the hydrolysis of PCr into Cr + Pi can be the liver and kidneys from arginine and glycine by the used as a buffer to resynthesize ATP [24, 25]. This helps enzyme arginine:glycine amidinotransferase (AGAT) to maintain ATP availability particularly during maximal ef- guanidinoacetate (GAA), which is then methylated by fort anaerobic sprint-type exercise. The CK/PCr system guanidinoacetate N-methyltransferase (GAMT) using also plays an important role in shuttling intracellular en- S-adenosyl methionine to form creatine (see Fig. 1) [12]. ergy from the mitochondria into the cytosol (see Fig. 2). Some individuals have been found to have creatine The CK/PCr energy shuttle connects sites of ATP produc- synthesis deficiencies due to inborn errors in AGAT, tion (glycolysis and mitochondrial oxidative phosphoryl- GMAT and/or creatine transporter (CRTR) deficiencies ation) with subcellular sites of ATP utilization (ATPases) and therefore must depend on dietary creatine intake in [24, 25, 27]. In this regard, creatine enters the cytosol order to maintain normal muscle and brain concentra- through a CRTR [16, 29–31]. In the cytosol, creatine and tions of PCr and Cr [13–19]. Vegetarians have been associated cytosolic and glycolytic CK isoforms help

Fig. 1 Chemical structure and biochemical pathway for creatine synthesis. From Kreider and Jung [6] Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 3 of 18

Fig. 2 Proposed creatine kinase/phosphocreatine (CK/PCr) energy shuttle. CRT = creatine transporter; ANT = adenine nucleotide translocator; ATP = adenine triphosphate; ADP = adenine diphosphate; OP = oxidative phosphorylation; mtCK = mitochondrial creatine kinase; G = glycolysis; CK-g = creatine kinase associated with glycolytic enzymes; CK-c = cytosolic creatine kinase; CK-a = creatine kinase associated with subcellular sites of ATP utilization; 1 – 4 sites of CK/ATP interaction. From Kreider and Jung [6]

Fig. 3 Role of mitochondrial creatine kinase (mtCK) in high energy metabolite transport and cellular respiration. VDAC = voltage-dependent anion channel; ROS = reactive oxygen species; RNS = reactive nitrogen species; ANT = adenine nucleotide translocator; ATP = adenine triphosphate; ADP = adenine diphosphate; Cr = creatine; and, PCr = phosphocreatine. From Kreider and Jung [6] Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 4 of 18

maintain glycolytic ATP levels, the cytosolic ATP/ADP ra- and protein have been reported to more consistently promote tio, and cytosolic ATP-consumption [27]. Additionally, cre- greater creatine retention [8, 22, 49, 50]. An alternative atine diffuses into the mitochondria and couples with ATP supplementation protocol is to ingest 3 g/day of creatine produced from oxidative phosphorylation and the adenine monohydrate for 28 days [7]. However, this method nucleotide translocator (ANT) via mitochondrial CK (see would only result in a gradual increase in muscle Fig. 3). ATP and PCr can then diffuse back into the cytosol creatine content compared to the more rapid loading and help buffer energy needs. This coupling also reduces method and may therefore have less effect on exercise the formation of reactive oxygen species (ROS) and can performance and/or training adaptations until creatine therefore act as a direct and/or indirect antioxidant [32– stores are fully saturated. Research has shown that 35]. The CK/PCr energy shuttle thereby connects sites of once creatine stores in the muscle are elevated, it ATP production (glycolysis and mitochondrial oxidative generally takes 4–6 weeks for creatine stores to re- phosphorylation) with subcellular sites of ATP utilization turn to baseline [7, 48, 51]. Additionally, it has been (ATPases) in order to fuel energy metabolism [24, 25, 27]. recommended that due to the health benefits of In this way, the CK/PCr system thereby serves as an creatine, individuals should consume about 3 g/day of important regulator of metabolism which may help explain creatine in their diet particularly as one ages [27]. No the ergogenic and potential therapeutic health benefits of evidence has suggested that muscle creatine levels fall creatine supplementation [4, 27, 33, 36–45]. below baseline after cessation of creatine supplemen- tation; therefore, the potential for long-term suppres- Supplementation protocols sion of endogenous creatine synthesis does not appear In a normal diet that contains 1–2 g/day of creatine, to occur [22, 52]. muscle creatine stores are about 60–80% saturated. Therefore, dietary supplementation of creatine serves to increase muscle creatine and PCr by 20–40% (see Fig. 4.) Bioavailability [7, 8, 10, 46–48]. The most effective way to increase The most commonly studied form of creatine in the muscle creatine stores is to ingest 5 g of creatine mono- literature is creatine monohydrate [53]. The uptake of hydrate (or approximately 0.3 g/kg body weight) four creatine involves the absorption of creatine into the times daily for 5–7 days [7, 10]. However, higher levels blood and then uptake by the target tissue [53]. Plasma of creatine supplementation for longer periods of time levels of creatine typically peak at about 60 min after may be needed to increase brain concentrations of creat- oral ingestion of creatine monohydrate [7]. An initial rise ine, offset creatine synthesis deficiencies, or influence in plasma creatine levels, followed by a reduction in disease states [13, 19, 23]. Once muscle creatine stores plasma levels can be used to indirectly suggest increased are fully saturated, creatine stores can generally be main- uptake into the target tissue [53]. However, the gold tained by ingesting 3–5 g/day, although some studies standards for measuring the effects of creatine supple- indicate that larger athletes may need to ingest as much mentation on target tissues are through magnetic resonance as 5–10 g/day in order to maintain creatine stores [7, 8, 10, spectroscopy (MRS), muscle biopsy, stable isotope tracer 46–48]. Ingesting creatine with carbohydrate or carbohydrate studies, and/or whole body creatine retention assessed by

Fig. 4 Approximate muscle total creatine levels in mmol/kg dry weight muscle reported in the literature for vegetarians, individuals following a normal diet, and in response to creatine loading with or without carbohydrate (CHO) or CHO and protein (PRO). From Kreider and Jung [6] Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 5 of 18

measuring the difference between creatine intake and urinary muscle availability of creatine and PCr and can there- excretion of creatine [53]. fore enhance acute exercise capacity and training Creatine is stable in solid form but not in aqueous so- adaptations in adolescents [62–66], younger adults lution due to an intramolecular cyclization [54]. Gener- [61, 67–77] and older individuals [5, 40, 43, 78–85]. ally, creatine is converted to creatinine at higher rates These adaptations would allow an athlete to do more the lower the pH and the higher the temperature. For work over a series of sets or sprints leading to greater example, research has shown that creatine is relatively gains in strength, muscle mass, and/or performance stable in solution at neutral pH (7.5 or 6.5). However, due to an improvement in the quality of training. after 3 days of storage at 25 °C, creatine degrades to cre- Table 2 presents the types of sport events in which atinine (e.g., 4% at pH 5.5; 12% at pH 4.5; and 21% at creatine supplementation has been reported to bene- pH 3.5) [53, 55]. The degradation of creatine into cre- fit. Creatine supplementation has primarily been rec- atinine over time is the main reason that creatine is sold ommended as an ergogenic aid for power/strength in solid form. However, this does not mean that creatine athletes to help them optimize training adaptations or is degraded into creatinine in vivo through the digestive athletes who need to sprint intermittently and recover process. In this regard, the degradation of creatine to during competition (e.g., American football, soccer, creatinine can be reduced or halted be either lowering basketball, tennis, etc.). After creatine loading, per- the pH under 2.5 or increasing the pH [53]. A very low formance of high intensity and/or repetitive exercise pH results in the protonation of the amide function of is generally increased by 10–20% depending on the the creatine molecule, thereby preventing the intra- magnitudeofincreaseinmusclePCr[46]. molecular cyclization [53]. Therefore, the conversion of Benefits have been reported in men and women, al- creatine to creatinine in the gastrointestinal tract is min- though the majority of studies have been conducted on imal regardless of transit time; absorption into the blood men and some studies suggest that women may not is nearly 100% [10, 53, 56, 57]. see as much gain in strength and/or muscle mass The vast majority of studies assessing the efficacy of during training in response to creatine supplementa- creatine supplementation on muscle phosphagen levels, tion [20, 51, 64, 86–90]. However, as will be de- whole body creatine retention, and/or performance have scribed below, a number of other applications in evaluated creatine monohydrate. Claims that different forms of creatine are degraded to a lesser degree than Table 2 Examples of sport events that may be enhanced by creatine supplementation creatine monohydrate in vivo or result in a greater up- Increased PCr take to muscle are currently unfounded [53]. Clinical • Track sprints: 60–200 m evidence has not demonstrated that different forms of • Swim sprints: 50 m creatine such as creatine citrate [50], creatine serum • Pursuit cycling Increased PCr Resynthesis [58], creatine ethyl ester [59], buffered forms of creatine • Basketball [60], or creatine nitrate [61] promote greater creatine re- • Field hockey tention than creatine monohydrate [53]. • America Football • Ice hockey • Lacrosse Ergogenic value • Volleyball Table 1 presents the reported ergogenic benefits of Reduced Muscle Acidosis • creatine supplementation. A large body of evidence Downhill skiing • Water Sports (e.g., Rowing, Canoe, Kayak, Stand-Up Paddling) now indicates that creatine supplementation increases • Swim events: 100, 200 m • Track events: 400, 800 m • Combat Sports (e.g., MMA, Wrestling, Boxing, etc.) Oxidative Metabolism Table 1 Potential ergogenic benefits of creatine • Basketball • Soccer supplementation • Team handball • Increased single and repetitive sprint performance • Tennis • Increased work performed during sets of maximal effort muscle • Volleyball contractions • Interval Training in Endurance Athletes • Increased muscle mass & strength adaptations during training Increased Body Mass/Muscle Mass • Enhanced glycogen synthesis • American Football • Increased anaerobic threshold • Bodybuilding • Possible enhancement of aerobic capacity via greater shuttling • Combat Sports (e.g., MMA, Wrestling, Boxing, etc.) of ATP from mitochondria • Powerlifting • Increased work capacity • Rugby • Enhanced recovery • Track/Field events (Shot put; javelin; discus; hammer throw) • Greater training tolerance • Olympic Weightlifting Adapted from Kreider and Jung [6] Adapted from Williams, Kreider, and Branch [269] Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 6 of 18

sport may benefit athletes involved in high intensity Other applications in sport and training intermittent and endurance events as well. In terms Recent research demonstrates a number of other appli- of performance, the International Society of Sports cations of creatine supplementation that may benefit Nutrition (ISSN) has previously concluded in its pos- athletes involved in intense training and individuals who ition stand on creatine supplementation that creatine want to enhance training adaptations. For example, use monohydrate is the most effective ergogenic nutri- of creatine during training may enhance recovery, re- tional supplement currently available to athletes in duce the risk of injury and/or help individuals recover terms of increasing high-intensity exercise capacity from injuries at a faster rate. The following describes and lean body mass during training [5, 78]. Recent some applications of creatine in addition to serving as position stands by the American Dietetic Association, an ergogenic aid. Dietitians of Canada, and the American College of Sports Medicine on nutrition for athletic performance Enhanced recovery all drew similar conclusions [91, 92]. Thus, a wide- Creatine supplementation can help athletes recover from spread consensus now exists in the scientific commu- intense training. For example, Green and coworkers [8] nity that creatine supplementation can serve as an ef- reported that co-ingesting creatine (5 g) with large fective nutritional ergogenic aid that may benefit amounts of glucose (95 g) enhanced creatine and carbo- athletes involved in numerous sports as well as indi- hydrate storage in muscle. Additionally, Steenge et al. viduals involved in exercise training. [49] reported that co-ingesting creatine (5 g) with 47– 97 g of carbohydrate and 50 g of protein enhanced creat- Prevalence of use in sport ine retention. Nelson and colleagues [104] reported that Creatine is found in high amounts in the food supply creatine loading prior to performing an exhaustive exer- and therefore its use is not banned by any sport cise bout and glycogen loading promoted greater glyco- organization although some organizations prohibit gen restoration than just carbohydrate loading alone. provision of some types of dietary supplements to ath- Since glycogen replenishment is important to promoting letes by their teams [5, 53, 78, 91, 92]. In these instances, recovery and preventing overtraining during intensified athletes can purchase and use creatine on their own training periods [78], creatine supplementation may help without penalty or violation of their banned substance athletes who deplete large amounts of glycogen during restrictions. Americans consume over four million kilo- training and/or performance to maintain optimal glyco- grams (kg) a year of creatine with worldwide use much gen levels. higher [53]. The reported prevalence of creatine use Evidence also suggests that creatine supplementation among athletes and military personnel in survey-based may reduce muscle damage and/or enhance recovery studies has generally been reported to be about 15–40% from intense exercise. For example, Cooke and associ- [93–101], with use more common in male strength/ ates [105] evaluated the effects of creatine supplementa- power athletes. High school athletes have been reported tion on muscle force recovery and muscle damage to have similar prevalence of use of creatine [95–97, 102]. following intense exercise. They reported that partici- In 2014, the NCAA reported that creatine was among the pants supplemented with creatine had significantly most popular dietary supplements taken by their male greater isokinetic (+10%) and isometric (+21%) knee ex- athletes (e.g., baseball - 28.1%, basketball - 14.6%, tension strength during recovery from exercise-induced football - 27.5%, golf - 13.0%, ice hockey - 29.4%, muscle damage. Additionally, plasma CK levels were sig- lacrosse - 25.3%, soccer 11.1%, swimming - 19.2%, nificantly lower (−84%) after 2, 3, 4, and 7 days of recov- tennis - 12.9%, track and field - 16.1%, wrestling - 28.5%) ery in the creatine supplemented group compared to whilefemaleathletesreportedauserateofonly0.2to controls. The authors concluded that creatine improved 3.8% in various sports [103]. Comparatively, these NCAA the rate of recovery of knee extensor muscle function athletes reported relatively high alcohol (83%), tobacco after injury. Santos and coworkers [106] evaluated the (10–16%), and marijuana (22%) use along with minimal effects of creatine loading in experienced marathon run- androgenic anabolic steroid use (0.4%). As will be noted ners prior to performing a 30 km race on inflammatory below, no study has reported any adverse or ergolytic markers and muscle soreness. The researchers reported effect of short- or long-term creatine supplementation that creatine loading attenuated the changes in CK while numerous studies have reported performance (−19%), prostaglandin E2 (−61%), and tumor necrosis and/or health benefits in athletes and individuals with factor (TNF) alpha (−34%) and abolished the increase in various diseases. Therefore, the prevalence of alcohol, lactate dehydrogenase (LDH) compared to controls. tobacco and drug use among NCAA athletes would Similar findings were reported by Demince et al. [107] seemingly be a much greater health concern than ath- who reported that creatine supplementation inhibited letes taking creatine. the increase of inflammatory markers (TNF-alpha and Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 7 of 18

C-reactive protein) in response to intermittent anaerobic tightness, muscle strains, and total injuries compared to sprint exercise. Finally, Volek and colleagues [77] eval- athletes who did not supplement their diet with creatine. uated the effects of creatine supplementation (0.3 g/ Likewise, Cancela and associates [113] reported that cre- kg/d) for 4 weeks during an intensified overreaching atine supplementation (15 g/day x 7-d, 3 g/day x 49-d) period followed by a 2 weeks taper. The researchers during soccer training promoted weight gain but that found that creatine supplementation was effective in those taking creating had no negative effects on blood maintaining muscular performance during the initial and urinary clinical health markers. Finally, Schroder et phase of high-volume resistance training overreaching al. [114] evaluated the effects of ingesting creatine (5 g/ that otherwise results in small performance decre- day) for three competitive seasons in professional bas- ments. These findings suggest that creatine supple- ketball players. The researchers found that long-term mentation can help athletes tolerate heavy increases low-dose creatine monohydrate supplementation did not in training volume. Therefore, there is strong evi- promote clinically significant changes in health markers dence that creatine supplementation can help athletes or side effects. Thus, contrary to unsubstantiated re- enhance glycogen loading; experience less inflamma- ports, the peer-reviewed literature demonstrates that tion and/or muscle enzyme efflux following intense there is no evidence that: 1) creatine supplementation in- exercise; and tolerate high volumes of training and/or creases the anecdotally reported incidence of musculo- overreaching to a greater degree thereby promoting skeletal injuries, dehydration, muscle cramping, recovery. gastrointestinal upset, renal dysfunction, etc.; or that 2) long-term creatine supplementation results in any clinic- Injury prevention ally significant side effects among athletes during train- Several studies have reported that creatine supplementa- ing or competition for up to 3 years. If anything, tion during training and/or competition either has no ef- evidence reveals that athletes who take creatine during fect or reduces the incidence of musculoskeletal injury, training and competition experience a lower incidence dehydration, and/or muscle cramping. For example, sev- of injuries compared to athletes who do not supplement eral initial studies on creatine supplementation provided their diet with creatine. 15–25 g/day of creatine monohydrate for 4 – 12 weeks in athletes engaged in heavy training with no reported Enhanced tolerance to exercise in the heat side effects [67, 77, 108–110]. Kreider and colleagues Like carbohydrate, creatine monohydrate has osmotic [109] reported that American collegiate football players properties that help retain a small amount of water. For ingesting 20 or 25 g/day of creatine monohydrate with a example, initial studies reported that creatine loading carbohydrate/protein supplement for 12 weeks during promoted a short-term fluid retention (e.g., about 0.5 – off season conditioning and spring football practice ex- 1.0 L) that was generally proportional to the acute perienced greater gains in strength and muscle mass weight gain observed [22, 46]. For this reason, there was with no evidence of any adverse side effects. Addition- interest in determining if creatine supplementation may ally, in a study specifically designed to assess the safety help hyper-hydrate an athlete and/or improve exercise of creatine supplementation, American collegiate foot- tolerance when exercising in the heat [76, 115–126]. For ball players ingesting about 16 g/day of creatine for 5 example, Volek and colleagues [76] evaluated the effects days and 5–10 g/day for 21 months had no clinically sig- of creatine supplementation (0.3 g/kg/day for 7 days) on nificant differences among creatine users and controls in acute cardiovascular, renal, temperature, and fluid- markers of renal function, muscle and liver enzymes, regulatory hormonal responses to exercise for 35 min in markers of catabolism, electrolytes, blood lipids, red cell the heat. The researchers reported that creatine supple- status, lymphocytes, urine volume, clinical urinalysis, or mentation augmented repeated sprint cycle performance urine specific gravity [22]. Meanwhile, creatine users in the heat without altering thermoregulatory responses. experienced less incidence of cramping, heat illness/de- Kilduff and associates [123] evaluated the effects of cre- hydration, muscle tightness, muscle strains/pulls, non- atine supplementation (20 g/day for 7 days) prior to per- contact injuries, and total injuries/missed practices than forming exercise to exhaustion at 63% of peak oxygen those not taking creatine [111]. uptake in the heat (30.3 °C). The researchers reported Similar findings were reported by Greenwood and co- that creatine supplementation increased intracellular workers [112] who examined injury rates during a 4 water and reduced thermoregulatory and cardiovascu- months American collegiate football season among cre- lar responses to prolonged exercise (e.g., heart rate, atine users (0.3 g/kg/day for 5 days, 0.03 g/kg/day for 4 rectal temperature, sweat rate) thereby promoting months) and non-users. The researchers reported that hyper-hydration and a more efficient thermoregulatory creatine users experienced significantly less incidence of response during prolonged exercise in the heat. Wat- muscle cramping, heat illness/dehydration, muscle son and colleagues [117] reported that short-term Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 8 of 18

creatine supplementation (21.6 g/day for 7 days) did colleagues [135] reported that creatine supplementation not increase the incidence of symptoms or comprom- (20 g/day for 6 days) did not enhance 800 m wheelchair ise hydration status or thermoregulation in dehy- performance in trained SCI wheelchair athletes. While drated (−2%), trained men exercising in the heat. not all studies show benefit, there is evidence that creat- Similar findings were observed by several other ine supplementation may help lessen muscle atrophy fol- groups [118, 119, 127, 128] leading researchers to add lowing immobilization and promote recovery during creatine to glycerol as a highly effective hyper- exercise-related rehabilitation in some populations. hydrating strategy to help athletes better tolerate ex- Thus, creatine supplementation may help athletes and ercise in the heat [116, 120–122, 125, 126]. These individuals with clinical conditions recover from injuries. findings provide strong evidence that creatine supplemen- tation (with or without glycerol) may serve as an effective Brain and spinal cord neuroprotection nutritional hyper-hydration strategy for athletes engaged The risk of concussions and/or SCI in athletes involved in intense exercise in hot and humid environments in contact sports has become an international concern thereby reducing risk to heat related-illness [5, 129]. among sports organizations and the public. It has been known for a long time that creatine supplementation Enhanced rehabilitation from injury possesses neuroprotective benefits [29, 38, 40, 136]. For Since creatine supplementation has been reported to this reason, a number of studies have examined the ef- promote gains in muscle mass and improved strength, fects of creatine supplementation on traumatic brain in- there has been interest in examining the effects of creat- jury (TBI), cerebral ischemia, and SCI. For example, ine supplementation on muscle atrophy rates as a result Sullivan et al. [137] examined the effects of 5 days of of limb immobilization and/or during rehabilitation creatine administration prior to a controlled TBI in rats [130]. For example, Hespel and coworkers [131] exam- and mice. The researchers found that creatine monohy- ined the effects of creatine supplementation (20 g/day drate ameliorated the extent of cortical damage by 36 to down to 5 g/day) on atrophy rates and rehabilitation 50%. The protection appeared to be related to creatine- outcomes in individuals who had their right leg casted induced maintenance of neuronal mitochondrial bio- for 2 weeks. During the 10 week rehabilitation phase, energetics. Therefore, the researchers concluded that participants performed three sessions a week of knee ex- creatine supplementation may be useful as a neuropro- tension rehabilitation. The researchers reported that in- tective agent against acute and chronic neurodegenera- dividuals in the creatine group experienced greater tive processes. In a similar study, Haussmann and changes in the cross-sectional area of muscle fiber associates [138] investigated the effects of rats fed creat- (+10%) and peak strength (+25%) during the rehabilita- ine (5 g/100 g dry food) before and after a moderate tion period. These changes were associated with greater SCI. The researchers reported that creatine ingestion im- changes in myogenic regulating factor 4 (MRF4) and proved locomotor function tests and reduced the size of myogenic protein expression. In a companion paper to scar tissue after the SCI. The authors suggested that pre- this study, Op’t Eijnde et al. [132] reported that creatine treatment of patients with creatine may provide neuro- supplementation offset the decline in muscle GLUT4 protection in patients undergoing spinal surgery who are protein content that occurs during immobilization and at risk to SCI. Similarly, Prass and colleagues [139] re- increased GLUT4 protein content during subsequent re- ported findings that creatine administration reduced habilitation training in healthy subjects. Collectively, brain infarct size following an ischemic event by 40%. these findings suggest that creatine supplementation Adcock et al. [140] reported that neonatal rats fed 3 g/ lessened the amount of muscle atrophy and detrimental kg of creatine for 3 days observed a significant increase effects on muscle associated with immobilization while in the ratio of brain PCr to Pi and a 25% reduction in promoting greater gains in strength during rehabilita- the volume of edemic brain tissue following cerebral tion. Similarly, Jacobs and associates [133] examined the hypoxic ischemia. The authors concluded that creatine effects of creatine supplementation (20 g/d for 7 days) supplementation appears to improve brain bioenergetics on upper extremity work capacity in individuals with thereby helping minimize the impact of brain ischemia. cervical-level spinal cord injury (SCI). Results revealed Similarly, Zhu and colleagues [141] reported that oral that peak oxygen uptake and ventilatory anaerobic creatine administration resulted in a marked reduction threshold were increased following creatine supplemen- in ischemic brain infarction size, neuronal cell death, tation. Conversely, Tyler et al. [134] reported that creat- and provided neuroprotection after cerebral ischemia in ine supplementation (20 g/day for 7 days, and 5 g/day mice. The authors suggested that given the safety record thereafter) did not significantly affect strength or func- of creatine, creatine might be considered as a novel tional capacity in patients recovering from anterior cru- therapeutic agent for inhibition of ischemic brain injury ciate ligament (ACL) surgery. Moreover, Perret and in humans. Allah et al. [142] reported that creatine Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 9 of 18

monohydrate supplementation for 10 weeks reduced the developmental delay/intellectual disability (DD/ID) with infarction size and improved learning/memory following speech/language delay and behavioral problems (n = 44), neonatal hypoxia ischemia encephalopathy in female epilepsy (n = 35), or movement disorder (n = 13). The mice. The authors concluded that creatine supplementa- median age at treatment was 25.5 months, 39 months, tion has the potential to improve the neuro-function fol- and 11 years in patients with mild, moderate, and severe lowing neonatal brain damage. Finally, Rabchevsky and DD/ID, respectively. The researchers found that creatine associates [143] examined the efficacy of creatine- supplementation increased brain creatine levels and im- supplemented diets on hind limb functional recovery proved or stabilized clinical symptoms. Moreover, four and tissue sparing in adult rats. Rats were fed a control patients treated younger than 9 months had normal or diet or 2% creatine-supplemented chow for 4–5 weeks almost normal developmental outcomes. Long-term cre- prior to and following SCI. Results revealed that creatine atine supplementation has also been used to treat pa- feeding significantly reduced loss of gray matter after tients with creatine deficiency-related gyrate atrophy SCI. These findings provide strong evidence that creat- [152–156]. These findings and others provide promise ine supplementation may limit damage from concus- that high-dose creatine monohydrate supplementation sions, TBI, and/or SCI [33, 144]. may be an effective adjunctive therapy for children and adults with creatine synthesis deficiencies [18, 145, 157– Potential medical uses of creatine 159]. Additionally, these reports provide strong evidence regarding the long-term safety and tolerability of high- Given the role of creatine in metabolism, performance, dose creatine supplementation in pediatric populations and training adaptations; a number of researchers have with creatine synthesis deficiencies, including infants less been investigating the potential therapeutic benefits of than 1 year of age [157]. creatine supplementation in various clinical populations. The following highlights some of these applications.

Neurodegenerative diseases Creatine synthesis deficiencies A number of studies have investigated the short and long- Creatine deficiency syndromes are a group of inborn er- term therapeutic benefit of creatine supplementation in rors (e.g., AGAT deficiency, GAMT deficiency, and children and adults with various neuromuscular diseases CRTR deficiency) that reduce or eliminate the ability to like muscular dystrophies [160–165], Huntington’s disease endogenously synthesize or effect transcellular creatine [23, 166–171]; Parkinson disease [23, 40, 166, 172–174]; transport [17]. Individuals with creatine synthesis defi- mitochondria-related diseases [29, 175–177]; and, ciencies have low levels of creatine and PCr in the amyotrophic lateral sclerosis or Lou Gehrig’sDisease muscle and the brain. As a result, they often have clin- [166, 178–184]. These studies have provided some ical manifestations of muscle myopathies, gyrate atrophy, evidence that creatine supplementation may improve movement disorders, speech delay, autism, mental exercise capacity and/or clinical outcomes in these retardation, epilepsy, and/or developmental problems patient populations. However, Bender and colleagues [13, 17, 145]. For this reason, a number of studies have in- [23] recently reported results of several large clinical vestigated the use of relatively high doses of creatine mono- trials evaluating the effects of creatine supplementa- hydrate supplementation (e.g., 0.3 – 0.8 g/kg/day equivalent tion in patients with Parkinson’s disease (PD), to 21 – 56g/dayofcreatinefora70kgperson,or1– 2.7 Huntington’s disease (HD), and amyotrophic lateral times greater than the adult loading dose) throughout the sclerosis (ALS). A total of 1,687 patients took an lifespan as a means of treating children and adults with cre- averageof9.5g/dayofcreatineforatotalof5,480 atine synthesis deficiencies [13, 17, 145–149]. These studies patient years. Results revealed no clinical benefit on generally show some improvement in clinical outcomes patient outcomes in patients with PD or ALS. How- particularly for AGAT and GAMT with less consistent ef- ever, there was some evidence that creatine supple- fects on CRTR deficiencies [145]. mentation slowed down progression of brain atrophy For example, Battini et al. [150] reported that a patient in patients with HD (although clinical markers were diagnosed at birth with AGAT deficiency who was unaffected). Whether creatine supplementation may treated with creatine supplementation beginning at 4 have a role in mediating other clinical markers in months of age experienced normal psychomotor devel- these patient populations and/or whether individual opment at 18 months compared to siblings who did not patients may respond more positively to creatine sup- have the deficiency. Stockler-Ipsiroglu and coworkers plementation than others, remain to be determined. [151] evaluated the effects of creatine monohydrate sup- Nevertheless, these studies show that creatine supple- plementation (0.3 – 0.8 g/kg/day) in 48 children with mentation has been used to treat children and adults GMAT deficiency with clinical manifestations of global with neurodegenerative conditions and is apparently Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 10 of 18

safe and well-tolerated when taking up to 30 g/day postmenopausal women. A recent meta-analysis [80] of for 5 years in these populations. 357 elderly individuals (64 years) participating in an aver- age of 12.6 weeks of resistance training found that partici- Ischemic heart disease pants supplementing their diet with creatine experienced Creatine and phosphocreatine play an important role in greater gains in muscle mass, strength, and functional maintaining myocardial bioenergetics during ischemic capacity. These findings were corroborated in a meta- events [33]. For this reason, there has been interest in analysis of 405 elderly participants (64 years) who experi- assessing the role of creatine or phosphocreatine in re- enced greater gains in muscle mass and upper body ducing arrhythmias and/or improving heart function strength with creatine supplementation during resistance- during ischemia [185–194]. In a recent review, Bales- training compared to training alone [37]. These findings trino and colleagues [33] concluded that phosphocrea- suggest that creatine supplementation can help prevent tine administration, primarily as an addition to sarcopenia and bone loss in older individuals. cardioplegic solutions, has been used to treat myocardial Finally, a number of studies have shown that creatine ischemia and prevent ischemia-induced arrhythmia and supplementation can increase brain creatine content improve cardiac function with some success. They sug- generally by 5 – 15% [218–220]. Moreover, creatine sup- gested that creatine supplementation may protect the plementation can reduce mental fatigue [221] and/or im- heart during an ischemic event. Thus, prophylactic cre- prove cognitive function [83, 222–225]. For example, atine supplementation may be beneficial for patients at Watanabe et al. [221] reported that creatine supplemen- risk for myocardial ischemia and/or stroke. tation (8 g/day for 5 days) reduced mental fatigue when subjects repeatedly performed a simple mathematical Aging calculation as well as increased oxygen utilization in the A growing collection of evidence supports that creatine brain. Rae and colleagues [222] reported that creatine supplementation may improve health status as individ- supplementation (5 g/day for 6 weeks) significantly uals age [41, 43–45, 195]. In this regard, creatine supple- improved working memory and intelligence tests re- mentation has been reported to help lower cholesterol quiring speed of processing. McMorris and co- and triglyceride levels [67, 196]; reduce fat accumulation workers [224] found that creatine supplementation in the liver [197]; reduce homocysteine levels [198]; (20 g/day for 7 days) after sleep deprivation demon- serve as an antioxidant [199–202]; enhance glycemic strated significantly less decrement in performance in control [132, 203–205]; slow tumor growth in some random movement generation, choice reaction time, types of cancers [32, 198, 206, 207]; increase strength balance and mood state suggesting that creatine im- and/or muscle mass [37, 41, 44, 45, 82, 208–212]; proves cognitive function in response to sleep minimize bone loss [211, 212]; improve functional cap- deprivation. This research group also examined the acity in patients with knee osteoarthritis [213] and fibro- effects of creatine supplementation (20 g/day for 7 myalgia [214]; positively influence cognitive function days) on cognitive function in elderly participants [43, 83, 195]; and in some instances, serve as an anti- and found that creatine supplementation significantly depressant [215–217]. improved performance on random number gener- For example, Gualano and associates supplemented ation, forward spatial recall, and long-term memory patients with type II diabetes with a placebo or creatine tasks. Ling and associates [225] reported that creat- (5 g/day) for 12 weeks during training. Creatine supple- ine supplementation (5 g/day for 15 days) improved mentation significantly decreased HbA1c and glycemic cognition on some tasks. Since creatine uptake by response to standardized meal as well as increased the brain is slow and limited, current research is in- GLUT-4 translocation. These findings suggest that creat- vestigating whether dietary supplementation of creat- ine supplementation combined with an exercise program ine precursors like GAA may promote greater improves glycemic control and glucose disposal in type increases in brain creatine [226, 227]. One recent 2 diabetic patients. Candow and others [211] reported study suggested that GAA supplementation (3 g/day) that low-dose creatine (0.1 g/kg/day) combined with increased brain creatine content to a greater degree protein supplementation (0.3 g/kg/day) increased lean than creatine monohydrate [227]. tissue mass and upper body strength while decreasing markers of muscle protein degradation and bone resorp- tion in older men (59–77 years). Similarly, Chilibeck et Pregnancy al. [212] reported that 12 months of creatine supplemen- Since creatine supplementation has been shown to tation (0.1 g/kg/day) during resistance training increased improve brain and heart bioenergetics during ische- strength and preserved femoral neck bone mineral dens- mic conditions and possess neuroprotective proper- ity and increased femoral shaft subperiosteal width in ties, there has been recent interest in use of creatine Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 11 of 18

during pregnancy to promote neural development and With regard to the question of whether creatine has reduce complications resulting from birth asphyxia effect on renal function, a few case studies [249–252] re- [228–237]. The rationale for creatine supplementation ported that individuals purportedly taking creatine with during pregnancy is that the fetus relies upon placental or without other supplements presented with high cre- transfer of maternal creatine until late in pregnancy and atinine levels and/or renal dysfunction [249–251]. Add- significant changes in creatine synthesis and excretion itionally, one study suggested that feeding rats with renal occur as pregnancy progresses [230, 232]. Consequently, cystic disease 2 g/kg/d of creatine for 1 week (equivalent there is an increased demand for and utilization of to 140 g/day for a 70 kg individual) and 0.4 g/kg/d creatine during pregnancy. Maternal creatine supple- (equivalent to 28 g/day for a 70 kg individual) for 4 mentation has been reported to improve neonatal sur- weeks exacerbated disease progression. These reports vival and organ function following birth asphyxia in prompted some concern that creatine supplementation animals [228, 229, 231, 233–235, 237]. Human studies may impair renal function [253–256] and prompted a show changes in the maternal urine and plasma creat- number of researchers to examine the impact of creatine ine levels across pregnancy and association to mater- supplementation on renal function [22, 51, 85, 114, 156, nal diet [230, 232]. Consequently, it has been 172, 243–248, 257–259]. For example, Ferreira and asso- postulated that there may be benefit to creatine sup- ciates [260] reported that creatine feeding (2 g/kg/d for plementation during pregnancy on fetal growth, devel- 10 weeks equivalent to 140 g/kg/d in a 70 kg person) opment, and health [230, 232]. This area of research had no effects on glomerular filtration rate and renal may have broad implications for fetal and child devel- plasma flow in Wistar rats. Likewise, Baracho and col- opment and health. leagues [261] reported that Wistar rats fed 0, 0.5, 1, or 2 g/kg/d of creatine did not result in renal and/or hep- atic toxicity. Poortmans and coworkers reported that Safety ingesting 20 g/day of creatine for 5 days [243], and up to Since creatine monohydrate became a popular dietary sup- 10 g/day from 10 months to 5 years [257] had no effect plement in the early 1990s, over 1,000 studies have been on creatine clearance, glomerular filtration rate, tubular conducted and billions of servings of creatine have been resorption, or glomerular membrane permeability com- ingested. The only consistently reported side effect from pared to controls. Kreider et al. [22] reported that creat- creatine supplementation that has been described in the lit- ine supplementation (5–10 g/day for 21 months) had no erature has been weight gain [5, 22, 46, 78, 91, 92, 112]. significant effects on creatinine or creatinine clearance Available short and long-term studies in healthy and dis- in American football players. Gualono and associates eased populations, from infants to the elderly, at dosages [262] reported that 12 weeks of creatine supplementa- ranging from 0.3 to 0.8 g/kg/day for up to 5 years have con- tion had no effects on kidney function in type 2 diabetic sistently shown that creatine supplementation poses no ad- patients. Finally, creatine supplement has been used as a verse health risks and may provide a number of health and means of reducing homocysteine levels and/or improv- performance benefits. Additionally, assessments of adverse ing patient outcomes in patients with renal disease event reports related to dietary supplementation, including [263–265] as well as ameliorating birth asphyxia related in pediatric populations, have revealed that creatine was renal dysfunction in mice [228]. Moreover, long-term, rarely mentioned and was not associated with any signifi- high dose ingestion of creatine (up to 30 g/d for up cant number or any consistent pattern of adverse events to 5 years) in patient populations has not been asso- [238–240]. Unsubstantiated anecdotal claims described in ciated with an increased incidence of renal dysfunc- thepopularmediaaswellasrarecasereportsdescribedin tion [23, 155, 156, 172]. While some have suggested the literature without rigorous, systematic causality assess- that individuals with pre-existing renal disease consult ments have been refuted in numerous well-controlled clin- with their physician prior to creatine supplementation ical studies showing that creatine supplementation does not in an abundance of caution, these studies and others increase the incidence of musculoskeletal injuries [22, 111, have led researchers to conclude that there is no 112, 241], dehydration [111, 112, 117, 122, 127–129, 242], compelling evidence that creatine supplementation muscle cramping [76, 106, 111, 112, 117], or gastrointes- negatively affects renal function in healthy or clinical tinal upset [22, 111, 112, 241]. Nor has the literature pro- populations [5, 6, 22, 53, 259, 266, 267]. vided any support that creatine promotes renal dysfunction Performance-related studies in adolescents, younger [22, 51, 85, 114, 156, 172, 243–248] or has long-term detri- individuals, and older populations have consistently re- mental effects [22, 23, 53, 155, 172]. Rather, as noted above, ported ergogenic benefits with no clinically significant creatine monohydrate supplementation has been found to side effects [5, 6, 22, 23, 53, 113, 129, 244, 245, 268]. reduce the incidence of many of these anecdotally reported The breadth and repetition of these findings provide side effects. compelling evidence that creatine monohydrate is well- Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 12 of 18

tolerated and is safe to consume in healthy untrained on otherwise healthy individuals or among clinical and trained individuals regardless of age. Moreover, as populations who may benefit from creatine noted above, the number of potential medical uses of supplementation. creatine supplementation that can improve health and 3. If proper precautions and supervision are provided, well-being as one ages and/or may provide therapeutic creatine monohydrate supplementation in children benefit in clinical populations ranging from infants to and adolescent athletes is acceptable and may senior adults has continued to grow without identifying provide a nutritional alternative with a favorable significant risks or adverse events even in these diseased safety profile to potentially dangerous anabolic or compromised special populations. It is no wonder androgenic drugs. However, we recommend that that Wallimann and colleagues [27] recommended that creatine supplementation only be considered for use individuals should consume 3 g/day of creatine through- by younger athletes who: a.) are involved in serious/ out the lifespan to promote general health. competitive supervised training; b.) are consuming a Some critics of creatine supplementation have pointed well-balanced and performance enhancing diet; c.) to warnings listed on some product labels that individ- are knowledgeable about appropriate use of creatine; uals younger than 18 years of age should not take creat- and d.) do not exceed recommended dosages. ine as evidence that creatine supplementation is unsafe 4. Label advisories on creatine products that caution in younger populations. It’s important to understand that against usage by those under 18 years old, while this is a legal precaution and that there is no scientific perhaps intended to insulate their manufacturers evidence that children and/or adolescents should not from legal liability, are likely unnecessary given the take creatine. As noted above, a number of short- and science supporting creatine’s safety, including in long-term studies using relatively high doses of creatine children and adolescents. have been conducted in infants, toddlers and adolescents 5. At present, creatine monohydrate is the most with some health and/or ergogenic benefit observed. extensively studied and clinically effective form of These studies provide no evidence that use of creatine at creatine for use in nutritional supplements in terms recommended doses pose a health risk to individuals less of muscle uptake and ability to increase high- than 18 years of age. Creatine supplementation may, how- intensity exercise capacity. ever, improve training adaptations and/or reduce risk to 6. The addition of carbohydrate or carbohydrate and injury, including in younger athletes. For this reason, it is protein to a creatine supplement appears to increase our view that creatine supplementation is an acceptable muscular uptake of creatine, although the effect on nutritional strategy for younger athletes who: a.) are in- performance measures may not be greater than volved in serious/competitive supervised training; b.) are using creatine monohydrate alone. consuming a well-balanced and performance enhancing 7. The quickest method of increasing muscle creatine diet; c.) are knowledgeable about appropriate use of creat- stores may be to consume ~0.3 g/kg/day of creatine ine; and d.) do not exceed recommended dosages. monohydrate for 5–7-days followed by 3–5 g/day thereafter to maintain elevated stores. Initially, Position of the international society of sports ingesting smaller amounts of creatine monohydrate nutrition (ISSN) (e.g., 3–5 g/day) will increase muscle creatine stores After reviewing the scientific and medical literature in over a 3–4 week period, however, the initial this area, the International Society of Sports Nutrition performance effects of this method of concludes the following in terms of creatine supplemen- supplementation are less supported. tation as the official Position of the Society: 8. Clinical populations have been supplemented with high levels of creatine monohydrate (0.3 – 0.8 g/kg/ 1. Creatine monohydrate is the most effective day equivalent to 21–56 g/day for a 70 kg individual) ergogenic nutritional supplement currently available for years with no clinically significant or serious to athletes with the intent of increasing high- adverse events. intensity exercise capacity and lean body mass dur- 9. Further research is warranted to examine the ing training. potential medical benefits of creatine monohydrate 2. Creatine monohydrate supplementation is not only and precursors like guanidinoacetic acid on sport, safe, but has been reported to have a number of health and medicine. therapeutic benefits in healthy and diseased populations ranging from infants to the elderly. There is no compelling scientific evidence that the Conclusion short- or long-term use of creatine monohydrate (up Creatine monohydrate remains one of the few nutritional to 30 g/day for 5 years) has any detrimental effects supplements for which research has consistently shown Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 13 of 18

has ergogenic benefits. Additionally, a number of potential founder of Supplement Safety Solutions, LLC, serving as an independent health benefits have been reported from creatine supple- consultant for regulatory compliance, safety surveillance and Nutravigilance to companies who sell creatine. Dr. Lopez is also co-inventor on multiple patent mentation. Comments and public policy related to applications within the field of dietary supplements, applied nutrition creatine supplementation should be based on careful as- and bioactive compounds. Remaining investigators have no competing sessment of the scientific evidence from well-controlled interests to declare. The comments and positions taken in this paper do not constitute an endorsement by institution’s the authors are affiliated. clinical trials; not unsubstantiated anecdotal reports, misinformation published on the Internet, and/or poorly Consent for publication designed surveys that only perpetuate myths about Not applicable. creatine supplementation. Given all the known benefits and favorable safety profile of creatine supplementation Ethics approval and consent to participate reported in the scientific and medical literature, it is the This paper was reviewed by the International Society of Sports Nutrition Research Committee and represents the official position of the Society. view of ISSN that government legislatures and sport orga- nizations who restrict and/or discourage use of creatine may be placing athletes at greater risk—particularly in Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in contact sports that have risk of head trauma and/or published maps and institutional affiliations. neurological injury thereby opening themselves up to legal liability. This includes children and adolescent athletes Author details 1Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department engaged in sport events that place them at risk for head of Health & Kinesiology, Texas A&M University, College Station, TX and/or spinal cord injury. 77843-4243, USA. 2Nutrition Research Unit, QPS, 6141 Sunset Drive Suite 301, Miami, FL 33143, USA. 3Department of Health and Human Performance, Acknowledgements Nova Southeastern University, Davie, FL 33328, USA. 4The Center for Applied We would like to thank all of the participants and researchers who Health Sciences, 4302 Allen Road, STE 120, Stow, OH 44224, USA. 5Post contributed to the research studies and reviews described in this position Active Nutrition, 111 Leslie St, Dallas, TX 75208, USA. 6Collins Gann stand. Your dedication to conducing groundbreaking research has improved McCloskey & Barry, PLLC, 138 Mineola Blvd., Mineola, NY 11501, USA. 7Faculty the health and well-being of countless athletes and patients. of Kinesiology and Health Studies, University of Regina, Regina, SK S4S 0A2, Prepared as a Position Stand on behalf of the International Society of Sport Canada. 8High Performance Nutrition, LLC, Mercer Island, WA 98040, USA. Nutrition with approval of Editors-In-Chief, Founders, and Research 9Vitargo Global Sciences, Inc., Dana Point, CA 92629, USA. 10Supplement Committee Members. Safety Solutions, LLC, Bedford, MA 01730, USA.

Funding Received: 27 April 2017 Accepted: 30 May 2017 Support to prepare this manuscript was provided by the Council for Responsible Nutrition. References Availability of data and materials 1. Bertin M, et al. Origin of the genes for the isoforms of creatine kinase. Not applicable. Gene. 2007;392(1–2):273–82. 2. Suzuki T, et al. Evolution and divergence of the genes for cytoplasmic, Authors’ contributions mitochondrial, and flagellar creatine kinases. J Mol Evol. 2004;59(2):218–26. RBK prepared the manuscript. Remaining coauthors reviewed, edited, and 3. Sahlin K, Harris RC. The creatine kinase reaction: a simple reaction with approved the final manuscript. The manuscript was then approved by the functional complexity. Amino Acids. 2011;40(5):1363–7. Research Committee and Editors-In Chief to represent the official position of 4. Harris R. Creatine in health, medicine and sport: an introduction to a the International Society of Sports Nutrition. meeting held at Downing College, University of Cambridge, July 2010. Amino Acids. 2011;40(5):1267–70. Competing interests 5. Buford TW, et al. International Society of Sports Nutrition position stand: RBK is a co-founder of the International Society of Sports Nutrition (ISSN) and creatine supplementation and exercise. J Int Soc Sports Nutr. 2007;4:6. has received externally-funded grants from industry to conduct research on 6. Kreider RB, Jung YP. Creatine supplementation in exercise, sport, and creatine, serves as a scientific and legal consultant, and is a university approved medicine. J Exerc Nutr Biochem. 2011;15(2):53–69. scientific advisor for Nutrabolt. He prepared this position stand update at the 7. Hultman E, et al. Muscle creatine loading in men. J Appl Physiol (1985). request of the Council for Responsible Nutrition and ISSN. DSK is a co-founder 1996;81(1):232–7. of the ISSN who works for a contract research organization (QPS). QPS has 8. Green AL, et al. Carbohydrate ingestion augments skeletal muscle creatine received research grants from companies who sell creatine. DSK sits in an accumulation during creatine supplementation in humans. Am J Physiol. advisory board (Post Holdings) to Dymatize that sells creatine. DSK declares no 1996;271(5 Pt 1):E821–6. other conflicts of interest. JA is the CEO and co-founder of the ISSN; has 9. Balsom PD, Soderlund K, Ekblom B. Creatine in humans with special consulted in the past for various sports nutrition brands. TNZ has received reference to creatine supplementation. Sports Med. 1994;18(4):268–80. grants and contracts to conduct research on dietary supplements; has 10. Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and served as a paid consultant for industry; has received honoraria for exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). speaking at conferences and writing lay articles about sports nutrition 1992;83(3):367–74. ingredients; receives royalties from the sale of several sports nutrition 11. Brosnan ME, Brosnan JT. The role of dietary creatine. Amino Acids. 2016; products; and has served as an expert witness on behalf of the plaintiff 48(8):1785–91. and defense in cases involving dietary supplements. TNZ is also co-inventor on 12. Paddon-Jones D, Borsheim E, Wolfe RR. Potential ergogenic effects of multiple patent applications within the field of dietary supplements, applied arginine and creatine supplementation. J Nutr. 2004;134(10 Suppl):2888S–94S. nutrition and bioactive compounds. RW is the Chief Science Officer for Post discussion 2895S. Active Nutrition. ALA is CEO of Vitargo Global Sciences, Inc., a company that 13. Braissant O, et al. Creatine deficiency syndromes and the importance of markets and sells a high insulinemic, starch-based carbohydrate. HLL has creatine synthesis in the brain. Amino Acids. 2011;40(5):1315–24. received research grants from companies who sell creatine and do business in 14. Wyss M, et al. Creatine and creatine kinase in health and disease–a bright the dietary supplement, natural products and medical foods industry. HLL is co- future ahead? Subcell Biochem. 2007;46:309–34. Kreider et al. Journal of the International Society of Sports Nutrition (2017) 14:18 Page 14 of 18

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Lancet. 1998;351(9111):1252–3. • Convenient online submission 252. Barisic N, et al. Effects of oral creatine supplementation in a patient with • Thorough peer review MELAS phenotype and associated nephropathy. Neuropediatrics. 2002;33(3): • Inclusion in PubMed and all major indexing services 157–61. • 253. Juhn MS, Tarnopolsky M. Potential side effects of oral creatine Maximum visibility for your research supplementation: a critical review. Clin J Sport Med. 1998;8(4):298–304. Submit your manuscript at www.biomedcentral.com/submit